Vascular diseases, such as cardiovascular, peripheral vascular and cerebral vascular, relating to or arising from lipid disorders, are a leading cause of death and disability in the developed world, particularly afflicting the elderly. Such diseases are a major cause of death in the affluent countries including the United States, where cardiovascular diseases are the cause of almost one million fatalities each year, more than one half of all deaths; almost 5 million persons afflicted with cardiovascular disease are hospitalized each year.
Arteriosclerosis refers to any group of diseases that are characterized by thickening and loss of elasticity in arterial walls. Of these diseases, atherosclerosis, the most common form of vascular disease, and coronary artery diseases have the most significant impact. Normally, the interior surface of the blood vessel is relatively smooth, allowing easy passage of the blood. In atherosclerosis, a common form of vascular disease, deposits of yellowish plaques (atheromas) containing cholesterol, fatty material, calcium, and lipid-filled macrophages are formed within the intima and inner media of large and medium-sized arteries. The plaque causes blockage of the blood vessel, facilitating clotting and leading to insufficient blood supply to critical body organs, which results in organ failures including heart attack, stroke, or kidney failure, and causing hypertension. Atherosclerosis underlies most coronary artery disease.
The very earliest phase of the development of atherosclerotic lesions (the fatty streak) involves the entry of monocytes into the subendothelial regions of the blood vessels. At the same time, low-density lipoprotein cholesterol (“LDL”) is retained in the subendothelial regions and is oxidized, causing these monocytes, now differentiated into macrophages, to uptake the oxidatively modified LDL, and stay localized. Such macrophages, or foam cells, increase in the size and their subsequent death and secretion of fibrous elements from the vascular smooth muscle cells (“VSMC”) contribute to the formation of the plaque. Atherosclerosis can be considered a hyperproliferative disease, wherein some of the normal VSMC in the artery wall become abnormally proliferative, and concurrently invading and spreading into the inner vessel lining, blocking blood flow and making that vessel abnormally susceptible to being completely blocked by local blood clotting. Such complete blockage may result in the death of the tissue served by that artery.
While elevation of the LDL level is generally unwanted and is considered detrimental to one's health, elevation of the HDL level is considered to be protective against atherosclerosis. HDL cholesterol is often referred to as “good” cholesterol since the negative association between serum HDL concentration and coronary heart disease is at least as strong as the positive association between low density lipoprotein (LDL) and coronary heart disease. Apolipoproteins A-I (“Apo A-I”) and A2 are the major apoprotein constituents of HDL, and have been considered to be anti-atherogenic due to their abilities to transport cholesterol from arteries to the liver for catabolism and excretion. See Furchart, J. and Ailhaud, G. (1992) Clin. Chem. 38:793-797.
Treatment of atherosclerosis includes management and reduction of the LDL cholesterol using drugs that are designed to inhibit cholesterol synthesis such as HMG-CoA reductase inhibitors (statins), nicotinic acid, bile salt sequestrants, or fibric acid derivatives. These pharmaceutical agents, however, are not without significant side effects. Statins are known to show various degrees of myotoxicity (Rosenson, (2004) Am. J. Med. 116(6):408-16), and nicotinic acid commonly induces vasodilatory effects. Fibrates are associated with a number of adverse effects, including liver enzyme elevations, gastrointestinal side effects and rhabdomyolysis (Muscari et al. (2002) Cardiology 97(3): 115-21).
Several Class A amphipathic helical peptide analogs of Apo A-I, which is derived from Apo A-I's eight tandem repeating 22-mer sequence, (Apo A-I mimetic peptides) have been shown to be effective against atherosclerotic development. The C-terminal portion of Apo A-I (residues 193 to 243) is thought to be actively involved in protein-lipid interactions. Apo A-I mimetic peptides enhance the ability of high-density lipoprotein (HDL) to protect low-density lipoprotein (LDL) from oxidation and remove seeding molecules from LDL. However, it is not clearly understood whether Apo A-I mimetic peptides protect LDL against oxidation independent of HDL-mediated mechanisms. Such peptides are generally rapidly degraded in vivo.
It has been previously shown that L-4F, an 18 L-amino acid-containing mimetic peptide, and its D-amino acid analog D-4F, block LDL oxidation and LDL-induced monocyte chemotactic activity. Furthermore, D-4F has been shown to be stable upon oral administration, resulting in almost 80% reduction of atherosclerotic lesions in LDL receptor-null mice. Navab et al., (2002) Circulation 105:290-292. L-4F and D-4F have a primary amino acid sequence Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2, (SEQ ID NO:1). The 18-mer has a potential to form a class A amphipathic helical structure (Segrest et al. (1974) FEBS Lett. 38:247-253). L-4F inhibits LDL and phospholipid oxidation through mechanisms independent of HDL-mediated processes.
Nevertheless, there is still a need for improved pharmaceutical agents to treat, prevent, or alter the progress of vascular disorders having a lipid based etiology, such as atherosclerosis, and generally to dyslipidemia, elevated cholesterol or decreased HDL.